X-linked hypophosphatemia (XLH) is characterized by increased FGF23, which impairs activation of vitamin D and promotes renal phosphate wasting leading to osteomalacia and rickets. Current treatment using 1,25- dihydroxyvitamin D(calcitriol) and phosphate is often complicated by hypercalcemia and nephrocalcinosis, and does not always prevent hyperparathyroidism. Furthermore, it does not normalize growth. Thus, we undertook a pre-clinical study in the Hyp mouse model of XLH, to compare the effects of calcitriol alone vs treatment with FGF23 blocking antibodies on growth, serum and urine mineral ions as well as histological, histomorphometric, microarchitectural and biomechanical properties of bones. These studies revealed that calcitriol monotherapy improves growth, prevents rickets and improves the microarchitectural and biomechanical properties of bone without phosphate supplementation. The beneficial effects of calcitriol were superior to those of the FGF23 blocking antibody employed, perhaps because, as in humans, FGF23 blocking antibodies were not able to sustain increased levels of 1,25-dihydroxyvitamin D. It is notable that the beneficial effects of calcitriol occur in spite of a significant increase in circulating FGF23 and bone FGF23 mRNA expression. Despite increased FGF23, calcitriol treatment decreases urinary phosphate clearance in Hyp mice. Thus, calcitriol has beneficial effects on bone and renal phosphate handling in XLH, in the setting of a further increase in FGF23. Based on these pre-clinical data, the current proposal aims to address the hypothesis that optimizing calcitriol therapy in humans with XLH, without phosphate supplementation, will have beneficial effects. We hypothesize that optimizing calcitriol will obviate the need for phosphate supplementation, thus increasing compliance and decreasing complications of current therapy which include nephrocalcinosis and hyperparathyroidism. Optimizing calcitrol therapy is also expected to improve skeletal microarchitecture in all subjects with XLH, and improve growth and prevent rachitic changes in pediatric subjects. Subjects with XLH will be recruited from adult and pediatric Endocrine and Nephrology clinics. Therapy will be stopped for 2 weeks, following which baseline labs will be obtained and calcitriol therapy will be initiated. The dose of calcitriol will be increased over a three-month period to identify the highest subject-specific dose that does not lead to hypercalcemia or hypercalciuria. Primary endpoints will be levels of serum phosphate, tubular resorption of phosphate (TmP/GFR), nephrocalcinosis score, and rickets score in children. The secondary endpoint will be growth in children. Data will be compared to subject-specific values obtained in the 24 months prior to optimization of calcitriol. Skeletal microarchitecture will be evaluated by high resolution peripheral qCT. The results of these investigations are expected to provide critical preliminary data for a large multicenter randomized clinical trial examining the comparative effectiveness of ?optimized calcitriol? to that of calcitriol plus phosphate, and to FGF23 blocking antibodies if they are FDA approved.